A novel treatable disorder of protein glycosylation; phosphoglucomutase 1 deficiency. E. Morava1, T. Marquardt2, J. Cegielska3, K. Raymond4, C. Stanley5, D. Lefeber6 1) Dept. of Pediatrics; Human Genetics Center, Tulane University, New Orleans, LA, US; 2) University of Munster, Department of Pediatrics, Munster, Germany; 3) University of Warsaw, Department of Pediatrics, Division of Metabolic and Endocrine Disorders, Poland; 4) Mayo Clinics, Mayo Laboratories, Rochester, NY, US; 5) The Childrens' Hospital of Philadelphia, Philadelphia, US; 6) Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

   We discovered a novel inborn error of glycosylation; phosphoglucomutase (PGM1) deficiency. Patients presented with cleft palate or uvula, hypoglycemia, endocrine abnormalities, cardiomyopathy and normal intelligence. The transferrin isoform pattern was pathognomic with decreased galactosylation, confirmed by mass spectrometry. PGM1 is a key enzyme between glycolysis and glycogenesis catalyzing the bidirectional transfer of phosphate from position 1 to 6 of glucose, leading to the production of Gluc-6-P. Gluc-1-P is connected to galactose metabolism, while UDP-glucose and UDP-galactose are essential activated sugars for normal protein glycosylation. The biochemical results of decreased glycosylation led us to evaluate the galactose intake in 8 patients with PGM1 deficiency. The amount of dietary galactose intake varied amongst patients, as did the degree of hypoglycosylation, determined by transferrin analysis. Patients with low galactose intake (less then 0.4g/kg/day) had increased tri-, di-, mono- and asialotransferrin at the time of diagnosis and had endocrine dysfunction. Variability in disease severity was hypothesized due to an altered balance between Gluc-1-P and Gal-1-P concentrations. Six patients consecutively underwent dietary intervention receiving either milk, or in case of milk aversion, oral lactose or galactose powder, according to WHO recommendations. After increasing galactose intake to the age appropriate range in patients, the transferrin pattern improved and galactosylation increased. In two cases, using an oral galactose powder supplement, liver function tests and endocrine dysfunction normalized in a year period. Patients on age appropriate milk intake and/or oral lactose supplement showed a significant improvement of secretory protein glycosylation, however no full restitution. One patient on lactose-supplemented diet needed diazoxide treatment due to recurrent hypoketotic hypoglycemia. We propose that PGM1 deficiency is a treatable subtype of the congenital disorders of glycosylation. We suggest that patients with galactose supplementation have a better clinical and biochemical outcome, compared to patients using dietary lactose. Since abnormal glycosylation in PGM1 defect is most likely the consequence of a decrease in the relative availability of the galactose building-units, necessary for the oligosaccharide chains of glycans, we propose age appropriate galactose supplementation in PGM1 deficient patients.

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